Potential profile generating method and protein tertiary structure prediction method and apparatus

Abstract

A method and apparatus for predicting a protein tertiary structure or designing a protein sequence using potential profiles calculated by using multidimensional singleton potentials dependent only on a residue type of one of residues of a residue pair and on a multidimensional relative structural relationship (including direction and orientation) between residues of each residue pair. Existing dynamic programming is used in predicting a protein tertiary structure.

1 . A potential profile generating method for obtaining energy values for each residue type in each of residue positions in a tertiary structure that is already known of a protein and generating a potential profile composed of information of the energy values for each residue type in each of residue positions, said method using multidimensional singleton potentials as potentials used in obtaining the energy values, wherein each of the singleton potentials is dependent on a multidimensional relative structural relationship and on a residue type of one of residues of a residue pair.  
     
     
         2 . A potential profile generating method comprising: 
 calculating an energy value of a residue at a residue position in a protein with a known tertiary structure using multidimensional singleton potentials dependent on a relative structural relationship of residues of a residue pair and on only a type of one of residues of the residue pair, while assuming each of the plurality of residues forms a residue pair with each of the other residues and further assuming a type of the residue as one of the residues;    obtaining a mean-force potential on the residue by adding energy values for all pairs calculated using the multidimensional singleton potentials, changing a type of the residue at the residue position to another type, and obtaining mean-force potentials for each of types of changed residues; and    executing processing for obtaining the mean-force potentials using singleton potentials for residues at the other positions in the protein with the known tertiary structure, and generating a potential profile of the protein with the known tertiary structure.    
     
     
         3 . A protein tertiary structure prediction method comprising: 
 preparing a plurality of template proteins with known tertiary structures, and obtaining potential profiles in advance for the template proteins using the method according to  claim 1  or  2 ;    applying a protein sequence of a protein whose tertiary structure is to be predicted to each of the plurality of template proteins with known tertiary structures to obtain optimal alignment, and obtaining an evaluation value that is a criterion to evaluate a degree of the optimal alignment for each of the template proteins; and    comparing the valuation value to each other with respect to the template proteins, estimating that a tertiary structure of a template protein with the highest evaluation value is similar to a tertiary structure of the protein sequence of the protein, and thereby predicting a protein tertiary structure.    
     
     
         4 . A protein sequence designing method comprising: 
 generating a potential profile of a protein having a desired structure and an unknown protein sequence using the method according to  claim 1  or  2 ; and    specifying a type (residue type) of a residue with the highest likelihood in each residue position using the potential profile, and thus determining a protein sequence.    
     
     
         5 . A protein tertiary structure prediction method comprising: 
 obtaining a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures;    calculating, by using the frequency distribution, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures, and adding energy values for each residue type to obtain mean-force potentials, with respect to each residue position of residue pairs of each template protein; and    evaluating a compatibility between a protein sequence of a prediction target protein with an unknown tertiary structure and a protein sequence of each template protein using the calculated mean-force potentials, and searching for a template protein having a tertiary structure similar to that of the prediction target protein.    
     
     
         6 . The method according to  claim 5 , wherein the multidimensional relative structural relationship includes at least two selected from among a distance between residues of a residue pair, a relative direction and relative orientation.  
     
     
         7 . The method according to  claim 6 , wherein the multidimensional relative structural relationship is a three-dimensional relationship comprising a distance r between residues of a residue pair, and directions θ and φ.  
     
     
         8 . The method according to  claim 5 , wherein when the frequency distribution of relative structural relationship is obtained, multidimensional frequency statistical processing is executed using an information compressing operation using Fourier expansion.  
     
     
         9 . The method according to  claim 8 , wherein in the information compressing operation using Fourier expansion, as linear bases of a distance direction component, Legendre Polynomial that is orthonormal in a designated area is used.  
     
     
         10 . The method according to  claim 5 , wherein in obtaining the mean-force potentials for each residue type, the mean-force potentials are obtained for each of the template proteins to generate potential profiles, and in evaluating a compatibility, compatibility between a protein sequence of the prediction target protein and each of the potential profiles is evaluated.  
     
     
         11 . The method according to  claim 10 , wherein in evaluating a compatibility between a protein sequence of the prediction target protein and each of the potential profiles, an average value is used as a compatibility evaluation value, the average value of mean-force potentials of residues at a residue position of a template protein corresponding to a residue type in the protein sequence and at a plurality of residue positions in the vicinity of the residue position.  
     
     
         12 . The method according to  claim 10 , wherein in evaluating a compatibility between a protein sequence of the prediction target protein and each of the potential profiles, optimal alignment of the potential profile with the residue is obtained using dynamic programming, and compatibility is evaluated based on an alignment score of the optimal alignment.  
     
     
         13 . The method according to  claim 12 , wherein in the dynamic programming, a bonus is added corresponding to a length of a consecutive matching region where insertion or lack is not present.  
     
     
         14 . A potential profile generating method for evaluating a compatibility between a protein sequence of a prediction target protein with an unknown structure and each of template proteins to search for a template protein with a tertiary structure similar to that of the prediction target protein, comprising: 
 obtaining a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures; and    calculating, by using the frequency distribution, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures, adding energy values for each residue type to obtain mean-force potentials, with respect to each residue position of residue pairs of each template protein, and obtaining mean-force potentials for each template protein to generate potential profiles.    
     
     
         15 . A protein tertiary structure prediction method comprising: 
 evaluating a compatibility between a potential profile using multidimensional singleton potentials dependent on a multidimensional relative structural relationship between residues obtained from a frequency distribution of known protein tertiary structures and only on a residue type of one of residues of a residue pair, and a protein sequence of a prediction target protein with an unknown tertiary structure; and    searching for a template protein having a tertiary structure similar to that of the prediction target protein based on the evaluation result.    
     
     
         16 . A protein tertiary structure predicting apparatus comprising: 
 a frequency distribution calculating section that calculates a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures;    a potential calculating section which with respect to each residue position of residue pairs of each template protein, calculates an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures, using the frequency distribution obtained in the frequency distribution calculating section, and adds energy values for each residue type to calculate mean-force potentials; and    a compatibility evaluating section that evaluates a compatibility between a reside sequence of a prediction target protein with an unknown structure and each of the template proteins using the mean-force potentials obtained in the potential calculating section.    
     
     
         17 . A potential profile generating apparatus for evaluating a compatibility between a protein sequence of a prediction target protein with an unknown structure and each of template proteins to search for a template protein with a tertiary structure similar to that of the prediction target protein, said apparatus comprising: 
 a distribution calculating section that calculates a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures; and    a potential profile generating section which with respect to each residue position of residue pairs of each template protein, calculates an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures, using the frequency distribution, adds energy values for each residue type to obtain mean-force potentials, and obtains mean-force potentials for each to generate a potential profile.    
     
     
         18 . A protein tertiary structure predicting apparatus comprising: 
 a compatibility evaluating section that evaluates a compatibility between a potential profile using multidimensional singleton potentials dependent on a multidimensional relative structural relationship between residues obtained from a frequency distribution of known protein tertiary structures and only on a residue type of one of residues of a residue pair, and a protein sequence of a prediction target protein with an unknown structure; and    a similar tertiary structure searching section that searches for a template protein having a tertiary structure similar to that of the prediction target protein based on the evaluation result.    
     
     
         19 . A program for making a computer execute the procedures of: 
 calculating a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures;    calculating, with respect to each residue position of residue pairs of each protein, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures using the frequency distribution, and adding energy values for each residue type to obtain mean-force potentials; and    evaluating a compatibility between a protein sequence of a prediction target protein with an unknown structure and each of the template proteins using stored mean-force potentials to search for a template protein likely having a tertiary structure similar to that of the template protein.    
     
     
         20 . A program which evaluates a compatibility between a protein sequence of a prediction target protein with an unknown structure and each of template proteins to search for a template protein with a tertiary structure similar to that of the prediction target protein, and which makes a computer execute the procedures of: 
 calculating a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures; and    calculating, with respect to each residue position of residue pairs of each protein, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures using the frequency distribution, adding energy values for each residue type to obtain mean-force potentials, and obtaining mean-force potentials for each template protein to generate potential profiles.    
     
     
         21 . A program for making a computer execute the procedures of: 
 evaluating a compatibility between a potential profile using multidimensional singleton potentials dependent on a multidimensional relative structural relationship between residues obtained from a frequency distribution of known protein tertiary structures and only on a residue type of one of residues of a residue pair, and a protein sequence of a prediction target protein with an unknown structure; and    searching for a template protein having a tertiary structure similar to that of the prediction target protein based on the evaluation result.    
     
     
         22 . A computer readable storage medium storing a program for making a computer execute the procedures of: 
 calculating a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures;    calculating, with respect to each residue position of residue pairs of each protein, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures using the frequency distribution, and adding energy values for each residue type to obtain mean-force potentials; and    evaluating a compatibility between a protein sequence of a prediction target protein with an unknown structure and each of the template proteins using stored mean-force potentials to search for a template protein likely having a tertiary structure similar to that of the template protein.    
     
     
         23 . A computer readable storage medium storing a program which evaluates a compatibility between a protein sequence of a prediction target protein with an unknown structure and each of template proteins to search for a template protein with a tertiary structure similar to that of the prediction target protein, and which makes a computer execute the procedures of: 
 calculating a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures; and    calculating, with respect to each residue position of residue pairs of each protein, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures using the frequency distribution and adding energy values for each residue type to obtain mean-force potentials, and obtaining mean-force potentials for each template protein to generate potential profiles.    
     
     
         24 . A computer readable storage medium storing a program for making a computer execute the procedures of: 
 evaluating a compatibility between a potential profile using multidimensional singleton potentials dependent on a multidimensional relative structural relationship between residues obtained from a frequency distribution of known protein tertiary structures and only on a residue type of one of residues of a residue pair, and a protein sequence of a prediction target protein with an unknown structure; and    searching for a template protein having a tertiary structure similar to that of the prediction target protein based on the evaluation result.    
     
     
         25 . A protein sequence designing method comprising: 
 obtaining a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures;    calculating, by using the frequency distribution, an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures, and adding energy values for each residue type to obtain mean-force potentials, with respect to each residue position of residue pairs of each template protein; and    specifying a type (reside type) of a residue with the highest likelihood in each residue position using obtained mean-force potentials, and thereby determining a protein sequence.    
     
     
         26 . The method according to  claim 25 , wherein the multidimensional relative structural relationship includes at least two selected from among a distance between residues of a residue pair, a relative direction and relative orientation.  
     
     
         27 . The method according to  claim 25 , wherein the multidimensional relative structural relationship is a three-dimensional relationship comprising a distance r between residues of a residue pair, and directions θ and φ.  
     
     
         28 . The method according to  claim 25 , wherein when a frequency distribution of relative structural relationship is obtained, multidimensional frequency statistical processing is executed using an information compressing operation using Fourier expansion.  
     
     
         29 . The method according to  claim 28 , wherein in the information compressing operation using Fourier expansion, as linear bases of a distance direction component, Legendre Polynomial that is orthonormal in a designated area is used.  
     
     
         30 . A protein sequence designing apparatus comprising: 
 a frequency distribution calculating section that calculates a frequency distribution of multidimensional relative structural relationship of each of all residue pairs of each protein from tertiary structure data of a plurality of proteins with known tertiary structures;    a potential calculating section which with respect to each residue position of residue pairs of each template protein, calculates an energy value based on multidimensional singleton potentials dependent on the multidimensional relative structural relationship and only on a residue type of one of residues of a residue pair, from tertiary structure data of a plurality of template proteins to be identified with known tertiary structures, using the frequency distribution obtained in the frequency distribution calculating section, and adds energy values for each residue type to obtain mean-force potentials; and    a protein sequence determining section that specifies a type of a residue (residue type) with the highest likelihood in each residue position using the mean-force potentials calculated in the potential calculating section, and thereby determines a protein sequence.    
     
     
         31 . A computer readable storage medium storing a program for making a computer execute a procedure of specifying a type of a residue (residue type) with the highest likelihood in each residue position to determine a protein sequence, using mean-force potentials obtained by using multidimensional singleton potentials dependent on a multidimensional relative structural relationship between residues obtained from a frequency distribution of known protein tertiary structures and only on a residue type of one of residues of a residue pair.